Recent observations in our laboratory have indicated that when the serum of patients with systemic lupus erythematosus (SLE) or with steroid toxicity is incubated with C3 nephritic factor (C3NeF), there is less C3 conversion, as measured by the loss of the B antigen to C3, than in serum from normal subjects (NHS). This was found to be the result of failure of formation of the alternative pathway convertase, C3b, Bb, a complex formed by factor D dependent activation of the Mg++ dependent complex, C3b,B. C3b,Bb formation has been measured in whole serum by the appearance of Ba, and alpha migrating fragment cleaved from factor B when it is activated by factor D. Preliminary studies have shown (a) that the amount of C3b,Bb formed in whole NHS in response to incubation with C3NeF is inversely related to the serum concentration of factor H, (b) for the level of factor H, C3b,Bb formation in the serum of patients with SLE or steroid toxicity in response to incubation with C3NeF is markedly depressed as compared with that in NHS, (c) that in these conditions, for the amount of C3b,Bb formed, C3 conversion is normal, (d) that increasing the Mg++ concentration of the serum increases C3b,Bb formation but the augmentation is relatively less in serum from SLE and steroid toxic patients than in NHS, (e) when the serum of many patients with SLE and steroid toxicity is mixed with an equal volume of NHS, C3b,Bb formation in response to incubation with C3NeF is less than the arithmetic mean of C3b,Bb formation in the two serum specimens incubated separately with C3NeF, indicating the presence of an inhibitor, and (f) that the severity of the inhibition of C3b,Bb formation in the serum of patients with SLE varies from patient to patient but appears to be independent of the status of the disease (active or in remission). Two aims of this project are to amplify the observations made on the serum of patients with SLE and steroid toxicity and to subject to similar study the serum of patients with conditions reported by others to be associated with depressed alternative pathway activity (severe burns, trauma, active rheumatoid arthritis, endotoxemia, and other forms of hypocomplementemic glomerulonephritis). The primary aim, however, will be to isolate the inhibitor found in patients with SLE, characterize it, determine its mode of action and raise an antibody to it which can be used to relate the inhibitor in SLE to that found in other conditions.